The metabolic syndrome is a major global health problem. In the US, the prevalence of metabolic syndrome in the adult population is currently estimated to be approximately 25%, and it continues to increase both in the US and worldwide. The metabolic syndrome is characterized by a combination of insulin resistance, dyslipidemia, obesity and hypertension leading to increased morbidity and mortality of cardiovascular diseases. People with the metabolic syndrome are at increased risk of developing frank type 2 diabetes mellitus, the frequency of which is equally escalating. In type 2 diabetes the combination of insulin resistance with obesity and dyslipidemia is also highly prevalent and around 70% of people with type 2 diabetes additionally have hypertension, once again leading to increased mortality of cardiovascular diseases.
In the clinical setting, it has long been known that glucocorticoids are able to induce all of the cardinal features of the metabolic syndrome and type 2 diabetes. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyses the local generation of active glucocorticoid in several tissues and organs including predominantly the liver and adipose tissue, but also e.g. skeletal muscle, bone, pancreas, endothelium, ocular tissue and certain parts of the central nervous system. Thus, 11β-HSD1 serves as a local regulator of glucocorticoid actions in the tissues and organs where it is expressed (Tannin et al., J. Biol., Chem., 266, 16653 (1991); Bujalska et al., Endocrinology, 140, 3188 (1999); Whorwood et al., J. Clin. Endocdnol. Metab., 86, 2296 (2001); Cooper et al., Bone, 27, 375 (2000); Davani et al., J. Biol. Chem., 275, 34841 (2000); Brem et al., Hypertension, 31, 459 (1998); Rauz et al., Invest. Ophthalmol. Vis. Sci., 42, 2037 (2001); Moisan et al., Endocrinology, 127, 1450 (1990)).
The role of 11β-HSD1 in the metabolic syndrome and type 2 diabetes is supported by several lines of evidence. In humans, treatment with the non-specific 11β-HSD1 inhibitor carbenoxolone improves insulin sensitivity in lean healthy volunteers and people with type 2 diabetes. Likewise, 11β-HSD1 knock-out mice are resistant to insulin resistance induced by obesity and stress. Additionally, the knock-out mice present with an anti-atherogenic lipid profile of decreased VLDL triglycerides and increased HDL-cholesterol. Conversely, mice that over-express 11β-HSD1 in adipocytes develop insulin resistance, hyperlipidemia, visceral obesity and hypertension, a phenotype that resembles the human metabolic syndrome (Andrews et al., J. Clin. Endocrinol. Metab., 88, 285 (2003); Walker et al., J. Clin. Endocrinol. Metab., 80, 3155 (1995); Morton et al., J. Biol. Chem. 276, 41293 (2001); Kotelevtsev et al., Proc. Natl. Acad. Sci. USA, 94,14924 (1997), Masuzaki et al., Science, 294, 2166 (2001), Masuzaki et al., J. Clin Invest, 112, 83 (2003)). 11β-HSD1 has also been demonstrated to play a role in increasing vessel wall contractility (Souness et al., Steroids 67, 195 (2002).
The more mechanistic aspects of 11β-HSD1 modulation and thereby modulation of intracellular levels of active glucocorticoid have been investigated in several rodent models and different cellular systems. 11β-HSD1 promotes the features of the metabolic syndrome by increasing hepatic expression of the rate-limiting enzymes in gluconeogenesis, namely phosphoenolpyuvate carboxykinase and glucose-6-phosphatase, promoting the differentiation of preadipocytes into adipocytes thus facilitating obesity, directly and indirectly stimulating hepatic VLDL secretion, decreasing hepatic LDL uptake and increasing vessel contractility, presumably by decreasing the levels of endothelial nitric oxide synthase and consequently the levels of the vasodialating substance nitric oxide (Kotelevtsev et al., Proc. Natl. Acad. Sci. USA, 94, 14924(1997); Morton et al., J. Biol. Chem. 276, 41293 (2001); Bujalska et al., Endocrinology, 140, 3188 (1999); Souness et al., Steroids, 67, 195 (2002); Brindley & Salter, Prog. Lipid Res., 30, 349 (1991); Whitworth et al., J. Hypertens. 20, 1035 (2002)).
Hence, 11β-HSD1 inhibitors constitute a new therapeutic principle for the treatment of insulin resistance, dyslipidemia, obesity and hypertension. In the clinical setting, however, monotherapeutic treatment of hypertension often lacks efficacy due, at least in part, to the induction of compensatory mechanisms.
The instant invention addresses this problem by providing a combination therapy comprising an 11β-HSD1 inhibitor and an antihypertensive agent for the treatment of e.g. the metabolic syndrome and type 2 diabetes. When administered as a part of a combination therapy, the 11β-HSD1 inhibitor together with the antihypertensive agent provide improved control of hypertension and/or improved treatment of the metabolic syndrome and type 2 diabetes thereby reducing the risk for late complications, e.g. cardiovascular diseases and nephropathy. Due to the greater benefit of the drug combination, lesser dosage amounts of the 11β-HSD1 inhibitor and more particularly the antihypertensive agent may be needed to achieve the desired clinical result, thereby resulting in improved safety.
Examples of inhibitors and/or modulators of the human 11β-hydroxysteroid dehydrogenase type 1 enzyme can be found in WO 01/90090, WO 01/90091, WO 01/90092, WO 01/90093, WO 01/90094, WO 02/72084 and WO 02/076435, as well as the following patent applications under common ownership of the present application: PA 2003 00569 filed 11 Apr. 2003 DK, PA 2003 00565 filed 11 Apr. 2003 DK, PA 2003 00571 filed 11 Apr. 2003 DK, PA 2003 00570 filed 11 Apr. 2003 DK, PA 2003 00566 filed 11 Apr. 2003 DK, PA 2003 00972 filed 27 Jun. 2003 DK, PA 2003 00998 filed 02 July 2003 DK, PA 2003 00988 filed 30 Jun. 2003 DK, PA 2003 00989 filed 30 Jun. 2003 DK, PA 2003 00990 filed 30 Jun. 2003 DK, and PA 2003 01910 filed 22 Dec. 2003 DK, the contents of which are hereby incorporated by reference in their entirety.